The use of lipoteichoic acid (LTA) from Streptococcus pyogenes to induce a serum factor causing tumour necrosis

Yamamoto, Akihiko; Usami, Hatsuhiko; Nagamuta, Masahiro; Sugawara, Yutaka; Hamada, Shigeyuki; Yamamoto, Toshiko; Kato, Kimiko; Kokeguchi, Susumu; Kotani, Shozo

doi:10.1038/bjc.1985.112

Cited by 41 publications

(13 citation statements)

References 14 publications

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“…Direct killing of cells by LTA was excluded in the present study (Table I). In a previous study (Yamamoto et al, 1985a), we demonstrated that the LTA of S. pyogenes was capable of inducing TNF in the sera of mice primed with P. acnes, and that the serum specimens induce haemorrhagic necrosis of pre-established MethA tumour. Since the cytotoxic factor (CF) induced by LTA was almost completely neutralized with anti-TNF serum, we believe CF induced by LTA is different from lymphotoxin (to be published).…”

Section: Discussionmentioning

confidence: 82%

Antitumour effects of streptococcal lipoteichoic acids on Meth A fibrosarcoma

Usami¹,

Yamamoto²,

Yamashita³

et al. 1988

Br J Cancer

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Summary The antitumour effects of lipoteichoic acids (LTA) extracted from Streptococcus pyogenes were studied in comparison with other streptococcal cellular components. LTA suppressed the tumour growth of both solid-and ascites-type MethA fibrosarcoma as did the whole cells of S. pyogenes . No OK-432, a streptococcal preparation, has been widely used to increase the resistance against tumours in experimental animals and cancer patients (Kurokawa et al., 1972;Sakurai et al., 1972). We have reported that OK-432, consisting of the whole organisms of S. pyogenes Su strain, significantly suppressed the growth of both ascites-and solid-type Meth A fibrosarcoma and Ehrlich carcinoma. The cytoplasmic membrane fraction prepared from the Su strain had an antitumour effect against the ascites variant but not against the solid tumour. In contrast, the isolated cell wall fraction acted as an antitumour agent against the solid tumour but not the ascitic variant (Koshimura et al., 1977;Yamamoto et al., 1980). These facts indicate that the antitumour principle of streptococcal whole cells lies in the cell wall and the cytoplasmic membrane. A possible candidate for such an antitumour principle is lipoteichoic acids (LTA), in view of the study by Wicken and Knox (1980) showing that LTA transects both the cell wall and the cytoplasmic membrane. There have been no previous reports on the antitumour effect of LTA.The purpose of the present study was to examine the antitumour effects of LTA in comparison with other streptococcal cellular components. Materials and methodsAnimals BALB/c (female, 6-8 weeks old) and CD-1 mice (female, 6-8 weeks old) were purchased from Charles River Japan Inc. (Atsugi, Kanagawa, Japan). water and then extracted with an equal volume of 95% phenol at room temperature for 1h. The water phase containing the LTA was separated by centrifugation at 6,000 g for 30 min, concentrated by evaporation under reduced pressure, and lyophilized. The resulting crude LTA was dissolved in 0.2 M ammonium acetate at 50 mg ml-1 and applied to a Sepharose 6B (Pharmacia, Uppsala Sweden) column (2.6 x 87 cm). The column was eluted with 0.2 M ammonium acetate to separate the LTA from polyglycerophosphate (PGP) and nucleic acids. The LTA fraction thus purified was lyophilized, and dissolved in pyrogen-free 0.85% NaCl solution before use. The purity of the LTA preparation was assessed by gas-liquid chromatography, and by chemical and immunochemical analyses as previously described (Hamada et al., 1985). Chemical analysis showed that the ratio of glycerol, fatty acids and alanine was consistent with the analytical data reported by Ofek et al. (1975). The colorimetric Limulus lysate assay with Toxicolor Test (Seikagakukogyo, Tokyo, Japan) indicated that 1 mg of the LTA preparation contained < 280 pg equivalent to a standard reference LPS (Bacto lipopolysaccharide W derived from Salmonella enteritidis). Other streptococcal components were obtained as follows: Peptidoglycan was prepared from S. pyogenes A374 according to the method d...

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Section: Discussionmentioning

confidence: 82%

Antitumour effects of streptococcal lipoteichoic acids on Meth A fibrosarcoma

Usami¹,

Yamamoto²,

Yamashita³

et al. 1988

Br J Cancer

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“…During the infection, S. aureus activates cells and evokes serious inflammation in the host. Lipoteichoic acid (LTA) 3 is a macroamphiphilic glycoconjugate distributing on the cell surface of Gram-positive bacteria and thought to be a virulence factor of Gram-positive bacteria (2). LTA are reported to exhibit immunostimulatory and inflammatory activities, including antitumor effect (3,4), and induce inflammatory cytokines, such as TNF, IL-1, and IL-6 (5-7).…”

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confidence: 99%

Not Lipoteichoic Acid but Lipoproteins Appear to Be the Dominant Immunobiologically Active Compounds in Staphylococcus aureus

Hashimoto

Tawaratsumida

Kariya

et al. 2006

The Journal of Immunology

208

203

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Lipoteichoic acid (LTA) derived from Staphylococcus aureus is reported to be a ligand of TLR2. However, we previously demonstrated that LTA fraction prepared from bacterial cells contains lipoproteins, which activate cells via TLR2. In this study, we investigated the immunobiological activity of LTA fraction obtained from S. aureus wild-type strain, lipoprotein diacylglycerol transferase deletion (Δlgt) mutant, which lacks palmitate-labeled lipoproteins, and its complemented strain and evaluated the activity of LTA molecule. LTA fraction was prepared by butanol extraction of the bacteria followed by hydrophobic interaction chromatography. Although all LTA fractions activated cells through TLR2, the LTA from Δlgt mutant was 100-fold less potent than those of wild-type and complemented strains. However, no significant structural difference in LTA was observed in NMR spectra. Further, alanylation of LTA molecule showed no effect in immunobiological activity. These results showed that not LTA molecule but lipoproteins are dominant immunobiologically active TLR2 ligand in S. aureus.

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“…LTA has been shown to have an antitumor effect (34,36) and to induce inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 (3,31,33). Recent research showed that such immunostimulatory activities of bacterial compounds were mediated by Toll-like receptor (TLR), a type I transmembrane receptor for innate immune activation (32).…”

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confidence: 99%

Evidence of Immunostimulating Lipoprotein Existing in the Natural Lipoteichoic Acid Fraction

Hashimoto¹,

Furuyashiki²,

Kaseya³

et al. 2007

Infect Immun

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Lipoteichoic acid (LTA) is a cell surface glycoconjugate of gram-positive bacteria and is reported to activate the innate immune system. We previously reported that purified LTA obtained from Enterococcus hirae has no immunostimulating activity, but a subfraction (Eh-AF) in an LTA fraction possesses activity. In this study, we established a mouse monoclonal antibody neutralizing the activity of Eh-AF and investigated its inhibitory effects. Monoclonal antibody (MAbEh1) was established by the immunization of BALB/c mice with Eh-AF, followed by hybridoma screening based on its inhibitory effect for the production of interleukin-6 (IL-6) induced by Eh-AF. MAbEh1 neutralized the production of IL-6 by LTA fraction from not only E. hirae but also Staphylococcus aureus, while it failed to block that of lipopolysaccharide, suggesting that the antibody recognized a common active structure(s) in LTA fractions. Synthetic glycolipids in these LTAs did not induce cytokine production, at least in our system. Interestingly, the antibody was found to inhibit the activity of immunostimulating synthetic lipopeptides, Pam 3 CSK 4 and FSL-1. These results suggest that MAbEh1 neutralizes the activity of lipoprotein-like compounds which is responsible for the activity of the LTA fraction of E. hirae and S. aureus.Lipoteichoic acid (LTA) is a macroamphiphile distributing on the cell surfaces of gram-positive bacteria and is reported to exhibit immunostimulatory and inflammatory activities. LTA has been shown to have an antitumor effect (34, 36) and to induce inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and 31,33). Recent research showed that such immunostimulatory activities of bacterial compounds were mediated by Toll-like receptor (TLR), a type I transmembrane receptor for innate immune activation (32). To date, more than 10 members of the TLR family have been discovered and most of their ligands were identified: TLR4 in combination with the adapter molecule MD-2 for lipopolysaccharide (LPS)/lipid A, an outer membrane component of gram-negative bacteria (21, 24); TLR9 for unmethylated CpG DNA (15); TLR3 and TLR7/8 for double-and single-stranded RNA (1, 14); TLR5 for bacterial flagellin (13); and TLR2 subfamily (TLR1, Ϫ2, and Ϫ6) for bacterial lipoprotein/lipopeptide (29, 30). LTA was also reported to be a ligand of TLR2 (22).The structures of LTAs have been well studied and proposed as a glycoconjugates generally composed of a glycolipid anchor part, such as ␤-kojibiosyldiacylglycerol for Enterococcus hirae and Streptococcus pyogenes and ␤-gentiobiosyldiacylglycerol for Staphylococcus aureus, and a 1,3-linked poly(glycerophosphate) substituted by sugars and D-alanine at position 2 of the glycerol (4). Previously, we attempted to determine a structure of the LTA responsible for these activities. Fukase et al. prepared chemically synthetic glycoconjugates having fundamental structures of LTA from E. hirae and S. pyogenes and their glycolipid anchor parts (5, 6). However, these synthetic compounds ...

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The use of lipoteichoic acid (LTA) from Streptococcus pyogenes to induce a serum factor causing tumour necrosis

Cited by 41 publications

References 14 publications

Antitumour effects of streptococcal lipoteichoic acids on Meth A fibrosarcoma

Antitumour effects of streptococcal lipoteichoic acids on Meth A fibrosarcoma

Not Lipoteichoic Acid but Lipoproteins Appear to Be the Dominant Immunobiologically Active Compounds in Staphylococcus aureus

Evidence of Immunostimulating Lipoprotein Existing in the Natural Lipoteichoic Acid Fraction

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